The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: Role of endogenous TLR ligands

Uaesoontrachoon, Kitipong, Cha, Hee-Jae, Ampong, Beryl, Sali, Arpana, Vandermeulen, Jack, Wei, Benjamin, Creeden, Brittany, Huynh, Tony, Quinn, James, Tatem, Kathleen, Rayavarapu, Sree, Hoffman, Eric P. and Nagaraju, Kanneboyina (2013) The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: Role of endogenous TLR ligands. Journal of Pathology, 231 2: 199-209. doi:10.1002/path.4207

Author Uaesoontrachoon, Kitipong
Cha, Hee-Jae
Ampong, Beryl
Sali, Arpana
Vandermeulen, Jack
Wei, Benjamin
Creeden, Brittany
Huynh, Tony
Quinn, James
Tatem, Kathleen
Rayavarapu, Sree
Hoffman, Eric P.
Nagaraju, Kanneboyina
Title The effects of MyD88 deficiency on disease phenotype in dysferlin-deficient A/J mice: Role of endogenous TLR ligands
Journal name Journal of Pathology   Check publisher's open access policy
ISSN 0022-3417
Publication date 2013
Year available 2013
Sub-type Article (original research)
DOI 10.1002/path.4207
Open Access Status
Volume 231
Issue 2
Start page 199
End page 209
Total pages 11
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley and Sons Ltd.
Collection year 2013
Language eng
Subject 2734 Pathology and Forensic Medicine
Abstract An absence of dysferlin leads to activation of innate immune receptors such as Toll-like receptors (TLRs) and skeletal muscle inflammation. Myeloid differentiation primary response gene 88 (MyD88) is a key mediator of TLR-dependent innate immune signalling. We hypothesized that endogenous TLR ligands released from the leaking dysferlin-deficient muscle fibres engage TLRs on muscle and immune cells and contribute to disease progression. To test this hypothesis, we generated and characterized dysferlin and MyD88 double-deficient mice. Double-deficient mice exhibited improved body weight, grip strength, and maximum muscle contractile force at 6-8 months of age when compared to MyD88-sufficient, dysferlin-deficient A/J mice. Double-deficient mice also showed a decrease in total fibre number, which contributed to the observed increase in the number of central nuclei/fibres. These results indicate that there was less regeneration in the double-deficient mice. We next tested the hypothesis that endogenous ligands, such as single-stranded ribonucleic acids (ssRNAs), released from damaged muscle cells bind to TLR-7/8 and perpetuate the disease progression. We found that injection of ssRNA into the skeletal muscle of pre-symptomatic mice (2 months old) resulted in a significant increase in degenerative fibres, inflammation, and regenerating fibres in A/J mice. In contrast, characteristic histological features were significantly decreased in double-deficient mice. These data point to a clear role for the TLR pathway in the pathogenesis of dysferlin deficiency and suggest that TLR-7/8 antagonists may have therapeutic value in this disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright
Keyword Degeneration
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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